Author Archives: churchc

The Application of Toxicogenomics for (Drinking) Water Quality Assessment

Water Intelligence Online;  Merijn Schriks, Corine Houtman and Ron van der Oost; 2014;  ISBN: 9781780406671

Due to anthropogenic activities, freshwater systems worldwide are exposed to thousands of compounds. Monitoring of priority pollutants is important, however, monitoring of all individual compounds would be practically impossible. Moreover, the effects on human health remains mostly unknown since compound toxicity data is often absent. With the release of increasing amounts of new (emerging) chemicals into the environment, new monitoring strategies are required to assess the effects of (drinking water relevant) chemicals on human health. Therefore, sensitive in-vitro bioassays have been developed which focus on specific physiological effects such as endocrine disruption or mutagenicity. The advantages of bioassays are that they directly determine the effect of (an entire mixture of) compounds present in an environmental sample instead of identifying single compounds. These bioassays are able to detect known and unknown compounds as long as they trigger the bioassay response. However, a disadvantage of applying these assays may be that they each focus on a (relatively narrow selection of) specific physiological endpoint and that the human relevance is often obscure.

The evolution of new technologies and the recent advances in the knowledge on DNA sequences and organisation (i.e. genomics) have enabled the development of new holistic tools, such as DNA microarrays.

This report provides an overview of innovative omic methods and the mechanisms behind certain genomics technologies are explained. The main focus is on the potential application of DNA microarrays that are able to measure the impact of toxic substances on gene expression, i.e. transcription of DNA to mRNA (transcriptomics). Practical information on this method, such as sensitivity, analysis time, responsiveness, specificity, etc. is discussed. An overview is presented of the potential applications of this technology with regard to water quality assessment. In addition, the limitations and challenges that need to be overcome are discussed.

The following potential applications for genomics in water quality assessment are foreseen:

• Prediction of the toxicity of compounds that are newly detected in aquatic samples and of which possible toxic properties and MOA are unknown.

• Environmental monitoring of toxic pressure at locations relevant for the water sector, such as drinking water intake locations. For this purpose, the No Observed Transcriptional Level (NOTEL) concept is a helpful concept to mutually compare different sites.

• Pre-screening of chemicals or locations for relevant toxicological effects, which can be investigated in more depth with specific bioassays.

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Are Bats Spreading Ebola Across Sub-Saharan Africa? [News and Analysis]

Science 11 April 2014:   Vol. 344 no. 6180 p. 140
DOI: 10.1126/science.344.6180.140

Ebola is not a stranger to West Africa—an outbreak in the 1990s killed chimpanzees and sickened one researcher. But the species of virus that has so far killed more than 100 people in Guinea has only been seen before in Central Africa. Scientists are combing the forests, and the genome of the virus itself, looking for clues to how this strain ended up so far west, and whether its spread suggests people in forested areas all across sub-Saharan Africa are at risk.

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Enhanced tetrazolium violet reduction of Salmonella spp. by magnesium addition to the culture media

Food Microbiology  Volume 42, September 2014, Pages 132–135;

Tetrazolium salts (TTZ), such as tetrazolium violet (TV), have been widely used for microbiological studies. The formation of the colored formazan product due to bacterial reduction of the uncolored reagent is extensively exploited to stain cells or colonies in agar or on filters. But an important toxic effect of tetrazolium salts on bacteria exists that limits their use at high concentrations, impairing the efficient staining of the colonies. This is especially the case for Salmonella spp. where we observed, using a classic photometric approach and mathematical modeling of the growth, an important impact of tetrazolium violet on the apparent growth rate below the inhibitory concentration. In this study, we demonstrate that adding magnesium to the medium in the presence of TV leads to a significant increase in the apparent growth rate. Moreover, when higher TV concentrations are used which lead to total inhibition of Salmonella strains, magnesium addition to the culture media allows growth and TV reduction. This effect of magnesium may allow the use of higher TTZ concentrations in liquid growth media and enhance bacteria detection capabilities.

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New insights into manganese toxicity and speciation

Journal of Trace Elements in Medicine and Biology Volume 28, Issue 2, April 2014, Pages 106–116;

Manganese (Mn) is known to be a neurotoxic agent for nearly 175 years now. A lot of research has therefore been carried out over the last century. From preliminary describing only symptoms of Mn-(over)exposed workers, research was preceded to more detail on toxic mechanisms of Mn. Unraveling those neurotoxic mechanisms implicated a number of studies, which were summarized partly in several reviews (e.g. Yokel RA. Neuromol Med 2009;11(4):297–310; Aschner M, et al. Toxicology Appl Pharmacol 2007;221(2):131–47; Michalke B, et al. J Environ Monit 2007;9(7):650). Since our recent review on Mn-speciation in 2007 (Michalke B, et al. J Environ Monit 2007;9(7):650), Mn-research was considerably pushed forward and several new research articles were published. The very recent years though, Mn toxicity investigating science is spreading into different fields with very detailed and complex study designs. Especially the mechanisms of Mn-induced neuronal injury on cellular and molecular level was investigated in more detail, discussing neurotransmitter and enzyme interactions, mechanisms of action on DNA level and even inclusion of genetic influences. Depicting the particular Mn-species was also a big issue to determine which molecule is transporting Mn at the cell membranes and which one is responsible for the injury of neuronal tissue. Other special foci on epidemiologic studies were becoming more and more important: These foci were directed toward environmental influences of Mn on especially Parkinson disease prevalence and the ability to carry out follow-up studies about Mn-life-span exposure. All these very far-reaching research applications may finally lead to a suitable future human Mn-biomonitoring for being able to prevent or at least detect the early onset of manganism at the right time.

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Toxicological properties of the thiolated inorganic arsenic and arsenosugar metabolite thio-dimethylarsinic acid in human bladder cells

Journal of Trace Elements in Medicine and Biology Volume 28, Issue 2, April 2014, Pages 138–146;

Thio-dimethylarsinic acid (thio-DMAV) has recently been identified as human metabolite after exposure toward both the human carcinogen inorganic arsenic and arsenosugars, which are the major arsenical constituents of marine algae. This study aims to get further insight in the toxic modes of action of thio-DMAV in cultured human urothelial cells. Among others effects of thio-DMAV on eight cell death related endpoints, cell cycle distribution, genotoxicity, cellular bioavailability as well as for the first time its impact on DNA damage induced poly(ADP-ribosyl)ation were investigated and compared to effects induced by arsenite. The data indicate that thio-DMAV exerts its cellular toxicity in a similar or even lower concentration range, however most likely via different mechanisms, than arsenite. Most interestingly, thio-DMAV decreased damage-induced cellular poly(ADP-ribosyl)ation by 35,000-fold lower concentrations than arsenite. The inhibition of this essential DNA-damage induced and DNA-repair related signaling reaction might contribute to inorganic arsenic induced toxicity, at least in the bladder. Therefore, and also because thio-DMAV is to date by far the most toxic human metabolite identified after arsenosugar intake, thio-DMAV should contemporary be fully (also in vivo) toxicologically characterized, to assess risks to human health related to inorganic arsenic but especially arsenosugar dietary intake.

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The Age of Radiance [Book Review]

Scientific American 310, 86 (2014)  Published online: 18 March 2014 | doi:10.1038/scientificamerican0414-86b

“Your family is radioactive; your friends are radioactive; your pets are radioactive; and the earth itself throws off a gaseous froth of radon,” writes journalist Nelson in this history of the atomic age. The book begins with the 1890s discovery of the first known radioactive elements and traces humankind’s manipulation of radiation through to the 2011 nuclear disaster in Fukushima, Japan.

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Ensuring privacy in the study of pathogen genetics

The Lancet Infectious Diseases Online 7 April 2014;

Rapid growth in the genetic sequencing of pathogens in recent years has led to the creation of large sequence databases. This aggregated sequence data can be very useful for tracking and predicting epidemics of infectious diseases. However, the balance between the potential public health benefit and the risk to personal privacy for individuals whose genetic data (personal or pathogen) are included in such work has been difficult to delineate, because neither the true benefit nor the actual risk to participants has been adequately defined. Existing approaches to minimise the risk of privacy loss to participants are based on de-identification of data by removal of a predefined set of identifiers. These approaches neither guarantee privacy nor protect the usefulness of the data. We propose a new approach to privacy protection that will quantify the risk to participants, while still maximising the usefulness of the data to researchers. This emerging standard in privacy protection and disclosure control, which is known as differential privacy, uses a process-driven rather than data-centred approach to protecting privacy.

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Bordetella holmesii: an under-recognised Bordetella species [Review]

The Lancet Infectious Diseases Online 7 April 2014;

Bordetella holmesii, first described in 1995, is believed to cause both invasive infections (bacteraemia, meningitis, endocarditis, pericarditis, pneumonia, and arthritis) and pertussis-like symptoms. Infection with B holmesii is frequently misidentified as being with B pertussis, the cause of whooping cough, because routine diagnostic tests for pertussis are not species-specific. In this Review, we summarise knowledge about B holmesii diagnosis and treatment, and assess research needs. Although no fatal cases of B holmesii have been reported, associated invasive infections can cause substantial morbidities, even in previously healthy individuals. Antimicrobial treatment can be problematic because B holmesii‘s susceptibility to macrolides (used empirically to treat B pertussis) and third-generation cephalosporins (often used to treat invasive infections) is lower than would be expected. B holmesii’s adaptation to human beings is continuing, and virulence might increase, causing the need for better diagnostic assays and epidemiological surveillance.

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Long-term exposures to low doses of cobalt nanoparticles induce cell transformation enhanced by oxidative damage

Nanotoxicology Online 9 April 2014;  doi:10.3109/17435390.2014.900582

A weak aspect of the in vitro studies devoted to get information on the toxic, genotoxic and carcinogenic properties of nanomaterials is that they are usually conducted under acute-exposure and high-dose conditions. This makes difficult to extrapolate the results to human beings. To overcome this point, we have evaluated the cell transforming ability of cobalt nanoparticles (CoNPs) after long-term exposures (12 weeks) to sub-toxic doses (0.05 and 0.1 µg/mL). To get further information on whether CoNPs-induced oxidative DNA damage is relevant for CoNPs carcinogenesis, the cell lines selected for the study were the wild-type mouse embryonic fibroblast (MEF Ogg1+/+) and its isogenic Ogg1 knockout partner (MEF Ogg1/), unable to properly eliminate the 8-OH-dG lesions from DNA. Our initial short-term exposure experiments demonstrate that low doses of CoNPs are able to induce reactive oxygen species (ROS) and that MEF Ogg1/ cells are more sensitive to CoNPs-induced acute toxicity and oxidative DNA damage. On the other hand, long-term exposures of MEF cells to sub-toxic doses of CoNPs were able to induce cell transformation, as indicated by the observed morphological cell changes, significant increases in the secretion of metalloproteinases (MMPs) and anchorage-independent cell growth ability, all cancer-like phenotypic hallmarks. Interestingly, such changes were significantly dependent on the cell line used, the Ogg1/ cells being particularly sensitive. Altogether, the data presented here confirms the potential carcinogenic risk of CoNPs and points out the relevance of ROS and Ogg1 genetic background on CoNPs-associated effects.

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Cytotoxicity of carbon nanotube variants: A comparative in vitro exposure study with A549 epithelial and J774 macrophage cells

Nanotoxicology Online 9 April 2014;  doi:10.3109/17435390.2014.902519

While production of engineered carbon nanotubes (CNTs) has escalated in recent years, knowledge of risk associated with exposure to these materials remains unclear. We report on the cytotoxicity of four CNT variants in human lung epithelial cells (A549) and murine macrophages (J774). Morphology, metal content, aggregation/agglomeration state, pore volume, surface area and modifications were determined for the pristine and oxidized single-walled (SW) and multi-walled (MW) CNTs. Cytotoxicity was evaluated by cellular ATP content, BrdU incorporation, lactate dehydrogenase (LDH) release, and CellTiter-Blue (CTB) reduction assays. All CNTs were more cytotoxic than respirable TiO2 and SiO2 reference particles. Oxidation of CNTs removed most metallic impurities but introduced surface polar functionalities. Although slopes of fold changes for cytotoxicity endpoints were steeper with J774 compared to A549 cells, CNT cytotoxicity ranking in both cell types was assay-dependent. Based on CTB reduction and BrdU incorporation, the cytotoxicity of the polar oxidized CNTs was higher compared to the pristine CNTs. In contrast, pristine CNTs were more cytotoxic than oxidized CNTs when assessed for cellular ATP and LDH. Correlation analyses between CNTs’ physico–chemical properties and average relative potency revealed the impact of metal content and surface area on the potency values estimated using ATP and LDH assays, while surface polarity affected the potency values estimated from CTB and BrdU assays. We show that in order to reliably estimate the risk posed by these materials, in vitro toxicity assessment of CNTs should be conducted with well characterized materials, in multiple cellular models using several cytotoxicity assays that report on distinct cellular processes.

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